The mechanisms regulating nerve cell excitability and the actions of ethanol on those mechanisms were investigated using electrophysiological methods. Current-clamp, voltage-clamp and patch-clamp studies were carried out on neurons in the central and peripheral nervous system and tissue culture cell lines to characterize the membrane ion channels involved in the regulation of nerve cell excitability. The following ion currents have been characterized on the basis of kinetics, voltage dependence and pharmacological sensitivity: (1) a transient inward sodium current; (2) a slower inward calcium current; (3) a fast transient calcium-dependent outward potassium current; (4) a slower transient voltage-dependent outward potassium current; (5) a rapidly activating, slowly decaying voltage-dependent outward potassium current; (6) a slowly activating, persistent calcium-dependent outward potassium current; (7) a slowly activating persistent outward potassium current that is inhibited by activation of muscarinic and certain peptide receptors; and (8) a rapidly activating inward potassium current that activates at membrane potentials negative to -70 mV. In hippocampal CA3 pyramidal neurons, 30-200 mM ethanol induced a concentration dependent increase in membrane excitability. In concentrations of 300 mM or greater, ethanol produced a decrease in membrane excitability. Voltage-clamp analysis of the membrane ion currents affected by ethanol revealed that 50-150 mM ethanol increased the persistent calcium-dependent potassium current. The significance of the project lies in the fact that the identification of the mechanisms involved in the regulation of nerve cell excitability and the action of ethanol on those mechanisms holds the promise of increasing our understanding of the cellular basis of ethanol's actions in the nervous system.